We have recently demonstrated that lncRNAs robustly regulate systemic lipid and glucose metabolism and their dysregulation might contribute to the pathogenesis of metabolic disease in mice (Li et al, Cell Metabolism, 2015, Ruan et al, Cell Reports, 2016 and Yang et al, Cell Metabolism, 2016). If lncRNAs play similar roles in humans, understanding their functions could provide important insights into human metabolic physiology and open up novel therapeutic strategies. However, lncRNAs are much less conserved among species and it is estimated that majority (81%) of human lncRNAs are either primate- or human-specific (Nature 2014 Jan 30; 505) and can only be adequately studied in human cells or tissues. To develop a system to study the role of human lncRNAs in energy metabolism in a pathophysiologically relevant setting, we have successfully produced liver-specific humanized mice in which over 90% mouse hepatocytes are replaced by engrafted human hepatocytes. We have used these mice to perform several genomewide screens and identified hundreds of human-specific lncRNAs implicated in metabolic regulation. Furthermore, we have showed that a number of selected lncRNAs robustly regulate the expression of key metabolic genes. We are currently investigating their physiological functions using the humanized mice and at the same time studying their mechanism of actions using RNA precipitation coupled with proteomics analysis and next generation sequencing.